The long-term objectives are to break the cycle of schistosomiasis transmission to humans, and to extend understanding of parasite strategies for survival in immunocompetent hosts. This is important because the occurrence of human schistosomiasis requires successful infection of the intermediate host snail Biomphalaria glabrata, so that interruption of the intra-molluscan stages of the life cycle could break the transmission cycle. Our hypothesis is that, in the early stages of molluscan schistosomiasis, products of the host hemocytes' respiratory burst and counter-defenses of the parasite are the major (but not exclusive) determinants of the parasite's fate. Specific aims are to determine the mechanisms responsible for the resistant and susceptible host phenotypes in the B. glabrata-Schistosoma mansoni PR-I strain host-parasite system, and to identify properties of this and other strains of the parasite that account for differences in infectivity. The distinctive fates of individual parasites in susceptible and resistant strains of host snail may be due to the combined effects of oxygen-independent and of oxygen- and nitrogen-dependent defense pathways of the host. The research will use in vitro models of parasite killing in which enzymes and products of these pathways will be measured and manipulated, gene transcript sequences will be obtained, and transcript levels will be determined in naive and challenged snails. The basis of a cost associated with resistance will be examined, and both proteomic and genomic approaches will be used to extend knowledge of gene products involved in determining compatibility. These studies will be done with both hosts and parasites. Differences in oxygen-independent cytotoxic mechanisms will be examined by both comparative proteomics and differential gene expression analyses. Tests of plausible hypotheses should lead to a better understanding of the mechanisms that lead to successful elimination of the parasite by resistant individuals of the molluscan host, and the means used by parasites to survive and proliferate while confronting the innate immune system of the mollusk. The suggested mechanisms may account for compatibility phenotypes in a broader range of strains and species, and for the recognized 'cost of resistance' in this parasitism.